The Risk of Ventricular Dysrhythmia or Sudden Death in Patients Receiving Serotonin Reuptake Inhibitors With Methadone: A Population-Based Study

Tony Antoniou; Daniel McCormack; Mina Tadrous; David N Juurlink; Tara Gomes

doi:10.3389/fphar.2022.861953

The Risk of Ventricular Dysrhythmia or Sudden Death in Patients Receiving Serotonin Reuptake Inhibitors With Methadone: A Population-Based Study

Front Pharmacol. 2022 Apr 20:13:861953. doi: 10.3389/fphar.2022.861953. eCollection 2022.

Authors

Tony Antoniou^{1

2

3

4}, Daniel McCormack⁴, Mina Tadrous^{4

5

6}, David N Juurlink^{4

7

8}, Tara Gomes^{2

4

5

9}

Affiliations

¹ Department of Family and Community Medicine, Unity Health Toronto, Toronto, ON, Canada.
² Li Ka Shing Knowledge Institute, Unity Health Toronto, Toronto, ON, Canada.
³ Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
⁵ Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
⁶ Women's College Research Institute, Toronto, ON, Canada.
⁷ Sunnybrook Research Institute, Toronto, ON, Canada.
⁸ Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁹ Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Abstract

Background: Methadone is associated with ventricular dysrhythmias and sudden death. Serotonin reuptake inhibitors (SRIs) may increase the risk of these events either by inhibiting metabolism of methadone's proarrhythmic (S)-enantiomer, additive QT interval prolongation, or both. We sought to determine whether certain SRIs were associated with a higher risk of methadone-related ventricular dysrhythmias or sudden death. Methods: We conducted a nested case-control study of Ontario residents receiving methadone between April 1, 1996 and December 31, 2017. Cases, defined as patients who died of sudden cardiac death or were hospitalized with a ventricular dysrhythmia while on methadone, were matched with up to four controls who also received methadone on age, sex, and a disease risk score. We determined the odds ratio (OR) and p-value functions for the association between methadone-related cardiotoxicity and treatment with SRIs known to inhibit metabolism of (S)-methadone (paroxetine, fluvoxamine, sertraline) or prolong the QT interval (citalopram and escitalopram). Patients who were not treated with an SRI served as the reference group. Results: During the study period, we identified 626 cases and 2,299 matched controls. Following multivariable adjustment, we found that recent use of sertraline, fluvoxamine or paroxetine (adjusted OR 1.30; 95% confidence intervals [CI] 0.90-1.86) and citalopram and escitalopram (adjusted OR 1.26; 95% CI 0.97-1.63) were associated with small increases in the risk methadone-related cardiac toxicity, an assertion supported by the corresponding p-value functions. Interpretation: Certain SRIs may be associated with a small increase in cardiac toxicity in methadone-treated patients.

Keywords: methadone; nested case control studies; pharmacoepidemiogy; serotonin reuptake inhibitor; sudden cardiac arrest.